Is TKT p.Pro194= (c.582A>G) pathogenic?

TKT p.Pro194= (c.582A>G) is classified Benign in TKT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-06-26). Common (popmax 29.2%, sas) — too common for a highly-penetrant pathogenic allele.

TKT p.Pro194=

Q: How common is TKT p.Pro194= (c.582A>G) in the general population?

TKT p.Pro194= (c.582A>G) is common (popmax 29.2%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.582A>G · rs1051485 · VCV1263760

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 29.2%, sas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -5.3
Overall
CADD	0.013	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 29.2% South Asian · 26,564/91,046 alleles

Filtering AF 28.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 28.8%

Overall 19.3% 311,821/1,613,630 alleles · common exomes 285,180/1,461,458 · genomes 26,641/152,172 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	29.2%	3
Finnishnot grpmax-eligible	21%	5
European (non-Finnish)	19.5%	5
Middle Eastern	19.5%	5
Remaining individualsnot grpmax-eligible	19%	5
Amishnot grpmax-eligible	17.1%	6
African / African-American	14.5%	7
Ashkenazi Jewishnot grpmax-eligible	13.9%	7
East Asian	13.2%	8
Admixed American	12.1%	8

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TKT
Protein: p.Pro194=
Coding: c.582A>G
MANE Select: NM_001064
dbSNP: rs1051485
Type: single nucleotide variant
Location: chr3:53235030 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.11 · 13 PDB
Residue 194: a turn

Full TKT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TKT p.Pro194Leu Uncertain significance ★ same residue
TKT p.Arg591Trp Uncertain significance ★★ ⚠ same type
TKT p.Asp106Tyr Uncertain significance ★★ ⚠ same type
TKT p.Leu153Pro Uncertain significance ★★ ⚠ same type
TKT p.Leu98Pro Uncertain significance ★★ ⚠ same type
TKT p.Tyr202Cys Uncertain significance ★★ same type
TKT c.1264+17T>C Benign ★★ same type
TKT c.1265-47G>C Benign ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tkt-p-pro194 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown